4 April 2019

A new approach to treating major depression

Mental Health

What is Transcranial Magnetic Stimulation?

Transcranial Magnetic Stimulation (TMS) is a technology initially created in 1985.1 TMS machines generate magnetic pulses and as with all magnetic fields, these pulses can penetrate solid non-conducting material such as bone.

In the same way MRI magnetic fields penetrate bone and tissue, TMS pulses do the same. When a TMS coil is placed over a person’s skull, the pulse emitted is strong enough to penetrate the skull and stimulate the underlying cortex. When these magnetic pulses turn on and off, they generate intrinsic electrical activity in the underlying neural matter.

The original TMS machines had the capacity to deliver one magnetic pulse at a time, enough to be used to research brain conductivity and potentially identify deficits or abnormalities.

In the 1990s, advances in the technology allowed for faster recharging of the coils and a capacity to deliver continuous repetitive pulsing. The amount of electricity needed to generate these rapid magnetic pulses creates significant heat, so to allow these coils to be used for more than a few minutes, modern TMS machines cool the coils, typically with either air or fluid.

Research studying the effect of repetitive TMS (rTMS) on the brain demonstrated a capacity for slow pulsing (1Hz or less) to decrease neural activity in the local area and rapid pulsing (10Hz or more) to increase that activity.

This discovery lead to a plethora of research looking at the capacity for rTMS to be used clinically.

By the late 1990s, placebo-controlled studies showed rTMS applied to the dorsolateral prefrontal cortex was helpful for treatment-resistant depression.

Since then the use of rTMS for this condition has been well established, being approved by the TGA for clinical use in Australia in 2007, and similarly by the FDA in the US.  In Australia and around the world, protocols for the treatment of mood disorders nowhave incorporated TMS as a second-line treatment for treatment-resistant depression.

In addition to its use in depression, rTMS has been investigated for many other neurological and psychiatric conditions and these studies are at varying stages of establishing clinical benefit.

Patient inclusion criteria for rTMS

Despite the wide use of pharmacotherapy in mood disorders, there remains a lack of clear guidance as to how to approach patients suffering from treatment-resistant depression.2 Comprehensive analyses of different combinations of medications and treatment regimens show that the more medication trials a patient experiences, the less likely they are to achieve remission.3

In contrast, the last decade has seen a proliferation of positive evidence for rTMS in this resistant group.

The Australian and New Zealand College of Psychiatrists guidelines suggest the use of rTMS as a second-line treatment once two anti-depressants have failed to show adequate improvement in depression. The treatment been shown to be effective in both unipolar and bipolar depression.

In addition, to the wealth of data supporting its use on treatment-resistant depression, there is an increasing body of evidence for the benefits of rTMS in anxiety disorders such as obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD).4 The treatment has been shown to be effective and well tolerated in the elderly and, in fact, may be an ideal choice for the elderly due to poorer responses to pharmacotherapy and increased complications with drug interactions.6

Some patients are excluded from treatment, including pregnant women and those patients with ferrous metallic substances such as staples, clips or cochlear implants in their brain.  Any metal that is fixed to bone, such as metal plates or dental braces, does not exclude patients from therapy. Similarly, metal items located below the neck, such as pacemakers, are not a contraindication for reatment.

As there is a one in 30,000 chance of a seizure during rTMS treatment, any patient who has unstable epilepsy would be excluded.

Finally, rTMS is currently only recommended for patients over the age of 18 years.

The largest barrier to accessing rTMS in Australia tends to be cost. Despite several RANZCP submissions to have rTMS attract a Medicare item number and rebate, the treatment has yet to be granted Medicare funding.

A treatment session lasting 45 minutes typically costs between $150 to $200. Patients are required to have between three to five sessions a week. A full course of 30 sessions will therefore take six to 10 weeks and cost between $4500 to $5500.

While this is a significant financial consideration, for many patients who have long-standing, depression which has failed to respond to all other available therapies, this treatment offers a real chance of recovery, that makes the cost worthwhile.

Effectiveness in a naturalistic clinical setting

While the safety and efficacy has been repeatedly shown,6 a study by Carpenter et al is important as it looked at the efficacy achieved by rTMS in a naturalistic clinical setting.7

This study enrolled 339 patients to perform outcome assessments during their usual clinical rTMS treatment. The majority of these patients received rTMS in a private clinical setting.

More than 90% of patients entering this study were classified as suffering from recurrent moderate to severe depression. It is important to note that this sample group had a four-fold higher incidence of prior psychiatric hospitalisation than is typically seen in phase III pharmaceutical studies, so is more reflective of patients typically seen by psychiatrists.

At the end point of this six-week study, the cumulative remission rates were 49-69% depending on the measurement tool used. While not designed to look at this, the study also showed an 83% adherence rate, with most patients receiving around 30 treatments.

Durability of benefits over 12-mth follow up

Clinicians often have questions about rTMS is in regard to the duration of effectiveness, the need for ongoing treatment, and response with repeated treatment. 

A multi-centre naturalistic study by Sackeim et al published in The Journal of Clinical Psychiatry, included 257 patients with pharmacotherapy resistant depression.8 These patients had never received rTMS and enrolled into a study looking at rTMS as an acute treatment.

Regardless of outcomes, the participants were subsequently enrolled into this 12 month follow-up study. As in the paper above, the majority of patients (76%) were treated in a private clinical setting. 

The results reinforce that rTMS is effective in treatment-resistant depression in a naturalistic setting with a 62.3% response rate and a 41.2% remission rate achieved at the six-week point (using CGI-S).

The treatment also showed impressive durability effect, with less than a third of the remitters and responders relapsing at the 12-month point.

Re-introduction of TMS in patients, who did relapse, again showed benefit for this group, with response rates being similar to their initial response.

Research also supports the value of rTMS as maintenance therapy, for those patients who do relapse.

Maintenance therapy can be administered initially weekly but gradually extended to one single session every four to six weeks. It is expected that about 30% of patients who respond well to rTMS would benefit from being on a maintenance program.

How does rTMS compare to electro-convulsive therapy?

Clearly rTMS is a safer and better tolerated treatment than electro-convulsive therapy (ECT), but how does it compare in efficacy? A meta-analysis by Micallef-Trigonais is the first to compare efficacy of rTMS and ECT in treatment-resistant unipolar and bipolar depression.9

This review included nine randomised clinical trials with a total of 384 patients.

Considering the treatment-resistant depression patient selection, both modalities did very well showing statistically significant reductions in Hamilton rating scale for depression of 9.3 for rTMS vs 15.4 for ECT.

Looking at the individual studies, three showed a clear advantage for ECT while the other seven showed no statistical difference between the two treatments.

While all the studies have limitations, particularly as they are largely conducted in naturalistic settings, they certainly suggest that in clinical settings, rTMS is a safe and effective treatment for treatment-resistant depression  that needs to be given more consideration by Australian clinicians. 

Where can a patient access rTMS and what do I need to tell my patients prior to referral?

The most important thing to tell patients prior to a referral is that rTMS is not ECT. Most patients have a horrific image of what ECT is and it is easy for them to immediately assume rTMS is the same thing.

Patients should be told that rTMS is a procedure that does not require hospitalisation and is done while they are fully awake in a regular doctor’s office. In our clinic (Sydney TMS) patients are encouraged to invite family and friends to attend the consultation.

Patients are not sedated in any way, so they are able to come on their own and drive before and after the procedure.

No fasting or stopping of medication is required. Patients are advised not to cease any current antidepressant medication they might be prescribed.

Typically, patients will start to show improvement after 20 to 25 TMS sessions, at which time a discussion about reducing concurrent medication can be had with the patient and the treating doctor.  Again at our clinic, treatment protocols are customised to the individual patients and these parameters are developed by the treating psychiatrist. Once all treatment parameters are established, the bulk of the treatment is administered by a trained rTMS nurse.

Patients are reviewed by a psychiatrist weekly during their course.

For more information, please visit www.sydneytms.com.au or call 1300 177 144.

Dr Jason Pace, FRANZCP, is owner of Sydney TMS

References:

1. Barker AT. An introduction to the basic principles of magnetic nerve stimulation. J Clin Neurophysiol 1991;8(1):26–37.

2. Sackeim HA. The definition and meaning of treatment-resistant depression. J Clin Psychiatry. 2001; 62 (suppl. 16):10–17.

3. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006; 163 (11):1905–1917

4. Rehn S et al. A Meta-Analysis of the Effectiveness of Different Cortical Targets Used in rTMS for the treatment of OCD. Psychiatr Q. 2018 Feb 9. Doi 10,1007/s11126-018-9566-7

5. Christine A. Conelea et al. Transcranial magnetic stimulation for treatment-resistant depression: Naturalistic treatment outcomes for younger versus older patients. Journal of Affective Disorders 217 ( 2017) 42-47.

6. Slotema C W et al.  Should we expand the toolbox of psychiatric treatment methods to include repetitive transcranial magnetic stimulation (rTMS)? A Meta-Analysis of the Efficacy of rTMS in Psychiatric disorders J Clin. Psychiatry 2010; 71(7): 873-884

7. Carpenter LL. Transcranial Magnetic Stimulation for Major Depression: A multisite naturalistic, observational study of acute treatment outcomes in clinical Practice. Depression and Anxiety 29:587-596 (2012).

8. Dunner D.L et al. A Multisite, Naturalistic, Observational Study of Transcranial Magnetic Stimulation for Patients with Pharmacoresistant Major Depressive Disorder: Durability of Benefit over a 1-Year Follow-Up Period. J Clin Psychiatry 2014; 75 (12):1394–1401

9. Micallef-Trigona B. Comparing the effect of repetitive transcranial magnetic stimulation and electroconvulsive therapy in the treatment of depression: A systematic review and Meta-Analysis. DepressionResearch and treatment, Vol 2014, Article ID 135049.